Tag Archives: safety testing

New publication: A New System to Assess New Chemicals for Endocrine Disruption

A groundbreaking new paper outlines a safety testing system that helps chemists design inherently safer chemicals and processes. Resulting from a cross-disciplinary collaboration among scientists, the innovative “TiPED” testing system (Tiered Protocol for Endocrine Disruption) provides information for making chemicals and consumer products safer. TiPED can be applied at different phases of the chemical design process, and can steer companies away from inadvertently creating harmful products, and thus avoid adding another BPA or DDT to commerce.

The 23 authors are biologists, green chemists and others from North America and Europe who say that recent product recalls and bans reveal that neither product manufacturers nor the government have adequate tools for dealing with endocrine disrupting chemicals (EDCs). EDCs are chemicals commonly used in consumer products that can mimic hormones and lead to a host of modern day health epidemics including cancers, learning disabilities and immune system disorders. The authors conclude that as our understanding of the threat to human health grows, the need for an effective testing strategy for endocrine disrupting chemicals becomes imperative.

Historically, chemists have aimed to make products that are effective and economical. Considering toxicity when designing new chemicals has not been their responsibility. This collaboration between fields expands the scope of both biologists and chemists to lead to a way to design safer chemicals.

Scientific understanding of endocrine disruption has developed rapidly over the past 2 decades, providing detailed, mechanistic insights into the inherent hazards of chemicals. TiPED uses these insights to guide chemical design toward safer materials. And as consumers are increasingly concerned about endocrine disruption (eg BPA, flame retardants) they are demanding products that do not contain EDCs, creating a market opportunity for companies that can take advantage of the new science.

There is a companion website to the paper, www.TiPEDinfo.com. One can access the paper there and learn more about the TiPED system.

New publication: A New System to Assess New Chemicals for Endocrine Disruption

A groundbreaking new paper outlines a safety testing system that helps chemists design inherently safer chemicals and processes. Resulting from a cross-disciplinary collaboration among scientists, the innovative “TiPED” testing system (Tiered Protocol for Endocrine Disruption) provides information for making chemicals and consumer products safer. TiPED can be applied at different phases of the chemical design process, and can steer companies away from inadvertently creating harmful products, and thus avoid adding another BPA or DDT to commerce.

The 23 authors are biologists, green chemists and others from North America and Europe who say that recent product recalls and bans reveal that neither product manufacturers nor the government have adequate tools for dealing with endocrine disrupting chemicals (EDCs). EDCs are chemicals commonly used in consumer products that can mimic hormones and lead to a host of modern day health epidemics including cancers, learning disabilities and immune system disorders. The authors conclude that as our understanding of the threat to human health grows, the need for an effective testing strategy for endocrine disrupting chemicals becomes imperative.

Historically, chemists have aimed to make products that are effective and economical. Considering toxicity when designing new chemicals has not been their responsibility. This collaboration between fields expands the scope of both biologists and chemists to lead to a way to design safer chemicals.

Scientific understanding of endocrine disruption has developed rapidly over the past 2 decades, providing detailed, mechanistic insights into the inherent hazards of chemicals. TiPED uses these insights to guide chemical design toward safer materials. And as consumers are increasingly concerned about endocrine disruption (eg BPA, flame retardants) they are demanding products that do not contain EDCs, creating a market opportunity for companies that can take advantage of the new science.

There is a companion website to the paper, www.TiPEDinfo.com. One can access the paper there and learn more about the TiPED system.

Heindel, center, goes to work creating a toxic pumpkin, while Tom Zoeller, Ph.D., left, and Wim Thielemans, Ph.D., take part in the fun. (Photo courtesy of Pete Myers)

Scientists committed to developing green solutions for replacing problem chemicals in the marketplace gathered Oct. 15-17 for a meeting on “Building the Path Forward for the Next Generation of Sustainable Chemicals,” held at the Rockefeller Brothers Fund Pocantico Center in Tarrytown, N.Y.

The meeting, sponsored by the non-government organizations Advancing Green Chemistry and Environmental Health Sciences, brought together a mixture of chemists, toxicologists, and biologists. Representatives from NIEHS and NTP included Division of Extramural Research and Training program administrators Jerry Heindel, Ph.D., and Thaddeus Schug, Ph.D.; Kristina Thayer, Ph.D., director of the newly named NTP Office of Health Assessment and Translation; and NTP Biomolecular Screening Branch Chief Ray Tice, Ph.D.

Designing safer chemicals

There are more than 83,000 chemicals in commerce today, many of which pose potential toxic hazards to human health and the environment. The challenge facing chemists designing replacement materials involves figuring out what kind of testing will need to be done to determine if the new chemical is safer than current ones to human health and the environment. One area of growing concern is how to ensure that the next generation of chemicals does not have the potential to act as endocrine disrupting compounds.

The meeting at Pocantico aimed to build upon a new set of testing tools — the Tiered Protocol for Endocrine Disruptors (TiPED) — developed by the group over the past two years. The protocol, which will be published online Dec. 6 in the Royal Society of Chemistry journal Green Chemistry, is not regulatory, but rather a tool to guide chemists as they develop a new chemical, to give them confidence as to whether the substance is or is not likely to be an endocrine disruptor.

The TiPED protocol offers a five-tiered approach, starting with what should be the fastest and cheapest assays, and working through increasingly specialized tests. The initial two phases rely on predictive computer modeling and high-throughput screening, to quickly weed out problem chemicals. These tests are followed by more specific in vitro cell-based screening assays with a goal of refining, reducing, and replacing animal testing as much as possible. The last two tiers are whole animal assays, to be used for looking for integrated endpoints and less understood systemic responses.

“The idea is that if chemists hit a positive early on, they would either go back to the drawing board or, if that positive was in a specific area, such as an estrogen receptor in a high throughput assay, they would follow that up with more comprehensive assays,” said Heindel. “A hit anywhere along the tiered system means chemists need to pull back, reanalyze, or throw the chemical out.”

The project emphasizes fundamental changes in the way that scientists design new chemicals, and in the process of bringing them into the marketplace. Chemists generally have little training in toxicology, so this plan offers guidelines they can follow early on in the product development process.

Moving forward with the plan

Following a team-building exercise on the evening of Oct. 15, involving pumpkins and toxicological design criteria, the first full day of the meeting was divided into discussion sessions aimed toward refining the specific testing strategies within each phase of the screening model. A good deal of time was dedicated to establishing criteria needed to assess the quality of assays within each tier of the protocol.

(Thaddeus Schug, Ph.D., is a health scientist in the NIEHS Division of Extramural Research and Training and a regular contributor to the Environmental Factor.)

Disclaimer: This report was written by members of the NIEHS staff based on materials prepared for this meeting and the discussions that took place there. It reflects the views of the authors and not necessarily those of the Rockefeller Brothers Fund, its trustees, or its staff.

The meeting was held on the ground floor of the Coach Barn of the Pocantico Center, which is also known as the John D. Rockefeller Estate. Take a video tour. (Photo courtesy of Ray Tice)

Tice, left, and Thayer take part in a discussion of the endocrine disruptor screening protocol. (Photo courtesy of Pete Myers)

The TiPED working group enjoyed the fall weather and the beautiful scenery at the Pocantico Center in Tarrytown, N.Y. (Photo courtesy of Ray Tice)

Small doses can have big health effects. That is a main finding of a new report, three years in the making, published Wednesday by a team of 12 scientists who study hormone-altering chemicals. Dozens of substances that can mimic or block hormones are found in the environment, the food supply and consumer products, including plastics, pesticides and cosmetics. One of the biggest controversies is whether the tiny doses that most people are exposed to are harmful. Researchers led by Tufts University’s Laura Vandenberg concluded after examining hundreds of studies that health effects “are remarkably common” when people or animals are exposed to low doses. “Fundamental changes in chemical testing are needed to protect human health,” they wrote.

By Marla Cone

Editor in Chief

Environmental Health News

March 15, 2012

Small doses can have big health effects.

That is a main finding of a report, three years in the making, published Wednesday by a team of 12 scientists who study hormone-altering chemicals.

Dozens of substances that can mimic or block estrogen, testosterone and other hormones are found in the environment, the food supply and consumer products, including plastics, pesticides and cosmetics. One of the biggest, longest-lasting controversies about these chemicals is whether the tiny doses that most people are exposed to are harmful.

In the new report, researchers led by Tufts University’s Laura Vandenberg concluded after examining hundreds of studies that health effects “are remarkably common” when people or animals are exposed to low doses of endocrine-disrupting compounds. As examples, they provide evidence for several controversial chemicals, including bisphenol A, found in polycarbonate plastic, canned foods and paper receipts, and the pesticide atrazine, used in large volumes mainly on corn.

The scientists concluded that scientific evidence “clearly indicates that low doses cannot be ignored.” They cited evidence of a wide range of health effects in people – from fetuses to aging adults – including links to infertility, cardiovascular disease, obesity, cancer and other disorders.

“Whether low doses of endocrine-disrupting compounds influence human disorders is no longer conjecture, as epidemiological studies show that environmental exposures are associated with human diseases and disabilities,” they wrote.

The scientists concluded that scientific evidence “clearly indicates that low doses cannot be ignored.” They cited evidence of a wide range of health effects in people – from fetuses to aging adults – including links to infertility, cardiovascular disease, obesity, cancer and other disorders.In addition, the scientists took on the issue of whether a decades-old strategy for testing most chemicals – exposing lab rodents to high doses then extrapolating down for real-life human exposures – is adequate to protect people.

They concluded that it is not, and so they urged reforms. Some hormone-like chemicals have health effects at low doses that do not occur at high doses.

“Current testing paradigms are missing important, sensitive endpoints” for human health, they said. “The effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.”

The report was published online Wednesday in the scientific journal Endocrine Reviews. Authors include scientists University of Missouri’s Frederick vom Saal, who has linked low doses of bisphenol A to a variety of effects, Theo Colborn, who is credited with first spreading the word about hormone-disrupting chemicals in the late 1980s and University of California, Berkeley’s Tyrone Hayes, who has documented effects of atrazine on frogs.

The senior author is Pete Myers, the founder of Environmental Health News and chief scientist of Environmental Health Sciences.

Linda Birnbaum, director of the National Institute of Environmental Health Sciences, said the new report is valuable “because it pulls a tremendous amount of information together” about endocrine-disrupting compounds. Her agency is the main one that studies health effects of contaminants in the environment.

Linda Birnbaum, director of the National Institute of Environmental Health Sciences, said in many cases, industry is still asking “old questions” about chemical safety even though “science has moved on.” Birnbaum said she agrees with their main finding: All chemicals that can disrupt hormones should be tested in ultra-low doses relevant to real human exposures, she said.

In many cases, chemical manufacturers still are asking “old questions” when they test the safety of chemicals even though “science has moved on,” she said. “Some of the testing paradigms have not advanced with the state of the science.” Birnbaum wrote an editorial on Wednesday referencing the new report.

Nevertheless, for most toxicologists, Birnbaum said the report does not offer a big shift from what they are doing. The NIEHS already conducts low-dose testing of chemicals, including looking for multi-generational effects such as adult diseases that are triggered by fetal exposures.

“Some people keep slamming the toxicologists. But you can’t paint everyone with the same brush,” Birnbaum said.

However, the scientists who wrote the report said that low-dose science “has been disregarded or considered insignificant by many.” They seemed to aim much of their findings at the National Toxicology Program and the U.S. Food and Drug Administration. The FDA in 2008 discounted low-dose studies when it concluded that bisphenol A (BPA) in consumer products was safe. Two years later, the agency shifted its opinion, stating that they now will more closely examine studies showing low-dose effects. The National Toxicology Program in 2008 found that BPA poses “some risks” to human health but rejected other risks because studies were inconsistent.

Several of the report’s authors have been criticized by some other scientists and industry representatives because they have become outspoken advocates for testing, regulating and replacing endocrine-disrupting compounds. The scientists, however, say they feel compelled to speak out because regulatory agencies are slow to act and they are concerned about the health of people, especially infants and children, and wildlife.

Industry representatives say that just because people are exposed to traces of chemicals capable of altering hormones doesn’t mean there are any harmful effects. They say that the studies are often contradictory or inconclusive.

“Based on the evidence, it is concluded that these ‘low dose’ effects have yet to be established [and] that the studies purported to support these cannot be validly extrapolated to humans.” -Michael Kamrin, Michigan State University In a statement, the American Chemistry Council, which represents chemical companies, said Wednesday that the industry “has committed substantial resources to advancing science to better understand any potential effects of chemical substances on the endocrine system. While we have not had an opportunity to fully review this paper, Michael Kamrin, emeritus professor of Michigan State University, has concluded ‘low dose’ effects have not been proven, and therefore should not be applied to real-world conditions and human exposures.”

“Based on the evidence, it is concluded that these ‘low dose’ effects have yet to be established [and] that the studies purported to support these cannot be validly extrapolated to humans,” Kamrin, a toxicologist, wrote in the International Journal of Toxicology in 2007.

But vom Saal and other scientists have said that tests that do not find low-dose effects of chemicals such as BPA are often industry-funded, and they often have tested the wrong animals or the wrong doses, or don’t expose the animals during the most vulnerable time of fetal growth.

Endocrinologists have long known that infinitesimal amounts of estrogen, testosterone, thyroid hormones and other natural hormones can have big health effects, particularly on fetuses. It comes as no surprise to them that manmade substances with hormonal properties might have big effects, too.

“There truly are no safe doses for chemicals that act like hormones, because the endocrine system is designed to act at very low levels,” Vandenberg, a postdoctoral fellow at Tufts University’s Levin Lab Center for Regenerative and Developmental Biology, told Environmental Health News.

But many toxicologists subscribe to “the dose makes the poison” conventional wisdom. In other words, it takes a certain size dose of something to be toxic. They also are accustomed to seeing an effect from chemicals called “monotonic,” which means the responses of an animal or person go up or down with the dose.

The scientists in the new review said neither of those applies to hormone-like chemicals.

“Accepting these phenomena should lead to paradigm shifts in toxicological studies, and will likely also have lasting effects on regulatory science,” they wrote.

In the report, the scientists were concerned that government has determined “safe” levels for “a significant number of endocrine-disrupting compounds” that have never been tested at low levels. They urged “greatly expanded and generalized safety testing.”

“Accepting these phenomena should lead to paradigm shifts in toxicological studies, and will likely also have lasting effects on regulatory science,” the scientists wrote.”We suggest setting the lowest dose in the experiment below the range of human exposures, if such a dose is known,” they wrote.

Vandenberg said that there may be no effect or a totally different effect at a high dose of a hormonal substance, while a lower dose may trigger a disease.

The breast cancer drug tamoxifen “provides an excellent example for how high-dose testing cannot be used to predict the effects of low doses,” according to the report. At low doses, it stimulates breast cancer growth. At higher ones, it inhibits it.

“Imagine taking 100 individuals that are representative of the American population and lining them up in order of exposure to an EDC [endocrine-disrupting compound] so that the person on the far left has the least exposure and the person on the far right has the most. For many toxic chemicals, individuals with the highest levels of exposure, at the right end of the line, have the highest incidence of disease. But for some EDCs, studies suggest that people in the middle of the line have the highest risk,” Vandenberg said.

She compared hormones, which bind to receptors in the body to trigger functions such as growth of the brain or reproductive organs, to keys in a lock.

“The more keys that are in the locks, the more of an effect that is seen. But at some point, the locks are overwhelmed and stop responding to the keys. Thus, in the lower range, more keys equals more of an effect, but in the higher range, more keys equals less of an effect,” she said.

Vandenberg predicted the report “will start conversations among academic, regulatory and industry scientists about how risk assessments for EDCs can be improved.”

“The question is no longer whether these phenomena exist, but how to move forward and deal with them.” Read more science at Environmental Health News.

Chemists developing compounds used to create fragrances can weed out chemicals that don’t meet toxicity and environmental standards early in the design process, finds a study that predicted the toxicity and persistence of a variety of musk chemicals using a sophisticated computer program.

The program – developed by the U.S. Environmental Protection Agency – uses molecular structure and other chemical attributes to predict if a compound will easily break down in the environment. The results are published in the journal Green Chemistry.

While the tools are not perfect, they help for early screening. One important use would be to compare the environmental effects of chemical classes or individual molecules to determine whether to proceed or block a chemical’s development. Further analysis and testing on the musks given the go ahead would still be needed to avoid producing a harmful molecule that might not be tagged as dangerous at this stage of development, because the computer modeling did not consider many potential mechanisms of toxicity, for example, whether or not the molecule is a potential endocrine disruptor.

The findings show that chemists can avoid making certain types of musks that may be harmful. Musks add scent to consumer products and can harm the environment. Predicting a compound’s later performance at a very early stage – even before the molecules are made – would make design and development of safer fragrance musks much cheaper.

Fragrances are used in a wide variety of products from the obvious perfumes to soaps, detergents, shampoos and toothpastes. The natural and synthetic musk compounds produce the rich and deep smells that form the base of some fragrances. The long-lived musks are chemically heavy and evaporate slowly. Their scents surface well after their use – at least 30 minutes – and may linger for a day. They also help hold lighter smells for a longer period of time.

These same longevity properties mean the compounds tend to end up in municipal wastewater and its solid sludge, which is often reused as fertilizer. Through these routes, musk compounds are released into the environment. They can accumulate in soils, wildlife and people. Several synthetic musks are toxic to fish, algae and aquatic invertebrates.

Chemists still design new synthetic musks. They use tools to predict the compounds’ future performances as a fragrance. A similar tool to predict their toxicity, their accumulation in the environment and their persistence in the environment is needed. A compound persists in the environment if it does not biodegrade.

The new research from the U.S. EPA looked at 106 synthetic and natural musk chemicals. The predictions on the environmental impact of these musks were compared to experimental data.

The study found and identified specific types of musks that were less problematic than others. It also verified that existing tools and knowledge could be used to screen new molecules for their potential to be toxic, not break down and accumulate.

According to the author, the research shows “that it can be convenient and useful to include environmental properties in that screening prior to any testing or manufacture of a chemical.” The tools and knowledge exist, and it is time to apply them to chemical production for “economic as well as environmental sense.”

On Wednesday November 9, 2011 UVA Green Chemistry hosted AGC’s Mana Sassanpour for a lecture and discussion on “What is Green Chemistry?”

Mana gave an overview of green chemistry, Paul Anastas and John Warner’s 12 principles of green chemistry, followed by a description of Advancing Green Chemistry’s involvement in the field.

Mana: “The discussion that followed after the lecture was phenomenal! Almost everyone who attended the lecture asked a question. I had never seen such an involved group of students!”

We started off discussing endocrine disrupting chemicals, for example: bisphenol A (BPA). What exposure level is safe? Really large amounts are harmful, but so are really tiny amounts – the correlation is not linear. We proceeded to discuss how we could test compounds for toxicity if the correlation is not linear. This led to a discussion on general methods for testing for toxicity, what the current standards are and how we could do better. We discussed the ethical concerns around animal testing and other tools.

The students were curious to find out what some of the common sources of BPA exposure are, and were surprised to find out that it is found in many disposable water bottles and plastic containers. A concerned student then asked for advice on how to avoid BPA. The response was: don’t use plastic food containers – but if you do, definitely do not microwave food in them because that allows the BPA and other contaminants to leach into your food. Store food in glass jars instead.

The ladies in the crowd then opened a discussion on cosmetics. Like many, they had never considered the chemicals in their beauty products. We talked about how many chapsticks and lip balms have oxybenzone in them – a component that acts as a sunscreen but is also a carcinogen. Most girls in the room immediately reached for their chapsticks to look at ingredients. A hand darted up to ask me “My chapstick has 6% oxybenzone – should I throw it away?” From this topic we went on to discuss how many sunscreen components do not degrade and go into our rivers and affect the reproductive anatomy of frogs and fish. This then led to how effects on amphibians predict effects on humans.

Needless to say, the conversation was great – filled with great facts, questions, and laughs!

With more than 83,000 chemicals available for use in the U.S. today, there is rising concern about potential toxic properties these chemicals pose in relation to human health and the environment. This issue has given rise to the field of green chemistry — the science-based design of chemicals to minimize the use and generation of hazardous substances.

Visioning a green future

The workshop brought together chemists, toxicologists, and biologists to define common goals, identify knowledge gaps, and promote applied research aimed at expediting the application of new approaches to toxicology to the emerging field of green chemistry. As he opened the meeting, NIEHS Toxicology Liaison and co-chair of the NSTC Subcommittee on Toxics and Risks Christopher Weis, Ph.D., challenged participants to think of a future with safer chemicals and less need for regulation.

Paul Anastas, Ph.D., assistant administrator of the U.S. Environmental Protection Agency Office of Research and Development, who is often referred to as the father of green chemistry, then set the stage for the meeting’s three sessions with a presentation, titled “Vision of a Green Chemical Future.” Anastas told participants, “There are tremendous advantages — environmental, economic, and health-related — in implementing green chemistry into the design and production of the next generation of chemicals.”

The main focus of the sessions centered on identifying replacements for problematic chemicals and the emerging tools available for toxicology testing. Representatives from industry, academia, and government agencies discussed the utility of rapid assessment approaches in toxicology, including high-throughput biochemical screening, in vitro cellular approaches, and rapid assessments using aquatic organisms.

Putting the plan to action

During session three, Thaddeus Schug, Ph.D., a postdoctoral fellow on detail to the NIEHS Division of Extramural Research and Training, highlighted a collaborative project that is constructing a protocol for chemists to flag endocrine disruptors early in chemical development. “The protocol is not regulatory,” Schug emphasized, “but a guide chemists can follow as they develop a chemical, to give them confidence as to whether the substance is or is not an endocrine disruptor.”

“What we propose to do is put the fastest, cheapest testing up front, the computational modeling, followed by high throughput screening and the zebrafish models,” Schug explained. The first-tier testing would be followed up with more specific testing as a chemical moves farther along the developmental process. (Photo courtesy of Steve McCaw)

“The idea is if chemists hit a positive early on, they would either go back to the drawing board, or if that positive was in a specific area, such as an estrogen receptor in a high throughput assay, they’d follow that up with more comprehensive assays,” Schug continued. “A hit anywhere along the tiered system means chemists need to pull back, reanalyze, or throw the chemical out.”

The protocol is voluntary, explainedBruce Blumberg, Ph.D., a professor of developmental and cell biology at the University of California, Irvine. “We suggest this if you want to screen for endocrine activity in your chemicals and make them more green – this is the way we think you should do it. We’re providing an alternative approach interested parties can use to make the best chemicals they can,” he said.

Richard Denison, Ph.D., senior scientist at Environmental Defense Fund, welcomed the protocol’s development, saying, “It really flips the concept of tiered testing around.” Usually in tiered testing, a chemical only advances to the next level of testing if it is flagged for an effect at an earlier level. “[That] puts a huge question mark around the extent to which false negatives are being missed,” Denison added.

“Dream big of a future in which green chemistry will move into the marketplace to the extent that this science will ultimately short-circuit the need for regulation,” Weis told workshop participants. “This will allow us to think ahead about potential chemical effects, rather than respond to problems that arise after chemicals are introduced.” (Photo courtesy of Steve McCaw)

The reporter got the attribution for our project wrong (NIEHS is not financially supporting this work, but is supporting it in kind. AGC and sister organization, Environmental Health Sciences, are funded to do the project). Still though: we are glad people are interested.

A group of biologists and green chemists, supported by the extramural research division of the National Institute of Environmental Health Sciences, is developing a protocol for chemists to use to determine if the chemical they are developing is an endocrine disruptor.

Thaddeus Schug, who manages a portfolio of grants in the NIEHS Cellular, Organs and Systems Pathobiology Branch, highlighted the project during a panel discussion on practical approaches to integrating rapid testing into the chemical design process. The discussion took place Sept. 21, the second day of a workshop, “Applying 21st Century Toxicology to Green Chemical and Material Design,” which was sponsored by the National Academies’ Standing Committee on Use of Emerging Science for Environmental Health Decisions. Schug says the group has been working for the last year on developing a protocol, and the guiding principles behind it, to determine whether a chemical under development is toxic, and how and where testing should be performed.

“We focus on endocrine disruption, but our guiding principles and protocol could be developed to capture all forms of toxicity,” he said. The protocol is not regulatory, Schug said, but a guide chemists can follow – as they develop a chemical – to give them confidence as to whether the substance is or is not an endocrine disruptor.

The group, which includes non-governmental organizations, academics and green chemistry leaders, has come up with a tiered system. “What we propose to do is put the fastest, cheapest testing up front – the computational modeling, followed by high throughput screening and the zebrafish models,” Schug said. That would be followed up with more specific testing as a chemical moves further along the development process.

“The idea is if a chemist hits a positive early on, he’d either go back to the drawing board, or if that positive was in a specific area [i.e. an estrogen receptor in a high throughput assay], he’d follow that up with more comprehensive assays,” Schug said. “A hit anywhere along the tiered system” means the chemist has to pull back, reanalyze or throw the chemical out, he said.
“The idea is to do the fastest, cheapest test early on, so the chemist can weed out those problem chemicals early on in development so it’s not a costly procedure,” Schug said.

The idea of the protocol “arose from a great sense of frustration” in the endocrine disruptor community, Bruce Blumberg, a professor of developmental and cell biology at the University of California, Irvine who also is working on the project, said during the panel discussion. This frustration stemmed from “hearing things like, ‘Well, you can’t test for endocrine disruptors,’ which the American Chemistry Council says,” Blumberg noted. “We know very well how to test for endocrine disruptors, how to test for endocrine disruptor activities from in vitro all the way to animal studies,” he said. “So we said this is a gap that has to be filled, and we got together to fill that gap.”

The protocol is voluntary, Blumberg noted. “We suggest this if you want to screen for endocrine activity in your chemicals and make them more green – this is the way we think you should do it. We’re providing an alternative approach interested parties can use to make the best chemicals they can,” he said.

Richard Denison, senior scientist at Environmental Defense Fund, welcomed the protocol’s development, saying “it really flips the concept of tiered testing around.”
Usually in tiered testing, a chemical only advances to the next level of testing if it is flagged for an effect at an earlier level, “which puts a huge question mark around the extent to which false negatives are being missed.”

But in the case of the protocol, “you’re advancing things that don’t raise red flags to the next level [of testing], increasing the confidence that you didn’t miss anything,” Denison said. “I think that’s a really intriguing approach.”
(Read full article here.)
– Liz Buckley

A representative diagram of the draft screening protocol unveiled at the meeting. The protocol is designed in a tiered approach, with rapid and cost effective screens conducted in the early phases and more extensive testing toward the end. (Slide courtesy of Pete Myers)

NIEHS/NTP scientists joined forces with leaders in the field of green chemistry in what may turn out to be a groundbreaking meeting, “Green Chemistry and Environmental Health Sciences — Designing Endocrine Disruption Out of the Next Generation of Materials,” held March 21-23 in Sausalito, Calif.

The challenges facing scientists trying to design such new materials are daunting. Say a chemist has developed a compound that he or she believes could be a replacement for bisphenol A (BPA). How will the scientist determine if the molecule is safer to human health and the environment? What testing will need to be done and what will guide scientists through this process?

The goals of the meeting in Sausalito were ambitious — to develop a consensus statement on the principles that guide the science needed to assess risks of potential endocrine disruptors, and to develop a reliable and rational testing protocol to aid chemists as they develop and bring the next generation of chemicals into the marketplace.

The intersection of green chemistry and environmental health science

Karen O’Brien, Ph.D., from Advancing Green Chemistry (AGC) and Pete Myers, Ph.D., of Environmental Health Sciences (EHS), welcomed participants to the event, which brought together an equal mix of biologists and chemists. Representatives from NIEHS and NTP included Division of Extramural Research and Training (DERT) program administrator Jerry Heindel, Ph.D., and Kristina Thayer, Ph.D., director of the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR).

Following a social ice-breaking exercise on the evening of March 21, the first full day of the meeting opened with presentations from Terry Collins, Ph.D., the Teresa Heinz Professor of Green Chemistry at Carnegie Mellon University, and John Warner, Ph.D., president and founder of the Warner Babcock Institute for Green Chemistry.

Both Collins and Warner stressed the need for fundamental changes in the way that scientists design new chemicals and the process of bringing them into the marketplace. “We must also pay close attention to the environmental impact and the effects on human health posed by these chemicals, and for those reasons chemists need to work hand-in-hand with biologists,” said Warner. He also stressed that chemists generally have no background in toxicology, but that they need to be able to test the chemicals being developed for endocrine activity and to do it early on in the product development process.

Designing a chemical screening protocol

The remainder of the day was divided into discussion sessions covering each phase of a newly developed screening model, designed by a science advisory board formed by meeting organizers that met monthly, via teleconference, for six months prior to the workshop. The protocol is geared towards identifying a wide-range of endocrine-active chemicals, such as atrazine, BPA, brominated flame retardants, organotins, perchlorates, and phthalates. The Board conducted interviews with scientists with expertise in specific areas of toxicology, endocrine disruption, and assay development.

The testing paradigm proposed involves a five-tiered approach, starting with the fastest and cheapest assays and working through more specialized tests to determine whether a new chemical has endocrine disrupting characteristics. The initial two phases rely on predictive computer modeling and high-throughput screening to quickly weed out problem chemicals. These tests are followed by more specific in vitro cell-based screening assays with a mind to refining, reducing, and replacing animal testing as much as possible.

The final two phases involve use of fish, amphibian, and mammalian in vivo modeling systems. Overall, the protocol is intended to help green chemists establish a high degree of confidence that the replacements they are developing are unlikely to be harmful to humans or the environment.

The next steps

The meeting wrapped up with discussion on how to proceed with development of the testing protocol as well as plans for implementation. The advisory board plans to use input from the meeting to develop and publish a white paper outlining guidelines that chemists can use to assess the quality of protocols and tests used to assess endocrine disruption.

(Thaddeus Schug, Ph.D., is a postdoctoral research fellow currently on detail as a program analyst in the NIEHS Division of Extramural Research and Training. He was part of the NIEHS/NTP delegation and a presenter at the meeting.)

Left to right, Collins, Heindel, and Warner mix ingredients for a batch of salmon tartare. The cooking exercise was used as an ice-breaking event to demonstrate how environmental health scientists and chemists can work together to solve complex issues. (Photo courtesy of Pete Myers)

Left to right, Bruce Blumberg, Ph.D., Thayer, and Andreas Kortenkamp, Ph.D., served as panel members for a discussion on in vitro screening assays. (Photo courtesy of Pete Myers)

A group photo of the meeting attendees. The meeting was held at the Cavallo Point Lodge, which sits adjacent to the Golden Gate Bridge. (Photo courtesy of Pete Myers)

NIEHS grantees Andrea Gore, Ph.D., left, and Frederick vom Saal, Ph.D., were among panel members for the discussion on in vivo assays. Both Gore and vom Saal are members of the project’s scientific advisory board. (Photo courtesy of Pete Myers)

Emerging Environmental Health Science in Green Chemistry

NIEHS Senior Advisor for Public Health John Balbus, M.D., attended the inaugural symposium March 24 for the new University of California, Berkeley Center for Green Chemistry, entitled “Green Chemistry: Collaborative Approaches and New Solutions.” Balbus’ talk, “Incorporating Emerging Environmental Health Science in Green Chemistry,” outlined some of the challenges of applying 21st century science to protect public health.

How do we harness the potential of unlocking the genome?

Can we more accurately predict which chemicals are likely to cause harm?

How do we implement our understanding of susceptibility and non-chemical stressors to enhance human health?

How can we better incorporate new methods and technologies into science policy?

Balbus proposed that the newly developed Tox21 (http://ntp.niehs.nih.gov/index.cfm?objectid=06002ADB-F1F6-975E-73B25B4E3F2A41CB), an interagency high throughput screening initiative, is aiming to meet many of these challenges and could be a valuable tool for green chemists. Demonstrating its utility in screening chemicals for disruptions in insulin signaling, Balbus concluded, “Advancements in programs such as Tox21 will eventually allow us to accurately predict how chemicals will impact human health before they are brought into the marketplace.”

A group of private and government scientists is moving closer to completing a testing protocol for determining whether new “green” chemicals entering the market are safer than those they are intended to replace and do not pose endocrine disruption risks, an effort that extends beyond EPA’s screening program, which focuses on existing chemicals.

Advancing Green Chemistry (AGC), the non-profit group leading the efforts, has joined with National Institute of Environmental Health Sciences (NIEHS), Environmental Health Sciences, Inc and other private sector groups, to develop a five-tiered testing protocol that will eventually be available free to chemical producers to determine whether their products may disrupt human endocrine systems, an outcome that has been linked to a slew of health problems including obesity and breast cancer.

An AGC source says the protocol is close to being submitted for peer review and developers hope it will be completed in about another year.

The protocol is designed to address concerns that newly developed green chemicals — which are intended to be safer alternatives than existing substances — may not be much better for the endocrine system, which regulates the body’s hormones, than the existing chemicals they are being created to replace.

While EPA is required by law to test a slew of existing chemicals under its endocrine disruptor screening program (EDSP), so far the agency has been “stuck” in what it can get done and has been struggling for almost two decades, the AGC source says.

Delays with the EPA program have long been a concern. For example, former House Rules Committee Chairman Louise Slaughter (D-NY) last year pushed legislation that would have created a new endocrine screening program at NIEHS, in part because EPA had been slow to establish its program. “While EPA does have the EDSP they’ve been more focused on toxics and only in the past few years focused on endocrine disruption,” her spokeswoman said (Risk Policy Report, Dec. 22, 2009).

Similarly, the AGC source says EPA is “snarled up in the morass of trying to regulate existing chemicals, and that hamstrings people.” Testing for endocrine disrupting effects “is something the government should be doing, but it just doesn’t seem to be something that’s happening,” the source says.

The source puts the blame on industry for the delays in EPA’s program. “There’s a lot of vested interest in the chemicals on the market” by their manufacturers, and that is slowing down the process, the source says. So far the agency “hasn’t been able to sort that out.” Rather than get bogged down in attempts for regulation of the chemicals, “we are trying to just look forward,” the source says.

But that is not to say that EPA hasn’t shown interest in the protocol. Paul Anastas, head of the Office of Research and Development, has been involved with developing the system, although the source says while he has been “constructive and supportive,” there has been no indication that EPA will adopt the methods. “But if they want to take over our project, great I think that would be better for all of us,” the source adds. “This should just be the way we test chemicals, period.”

A second source, however, argues that EPA’s programs aren’t capable of looking at such sensitive effects of chemicals. “Unfortunately there are people still working in the lab in EPA . . . who will say none of this work has any value,” the source continues. “They are stuck with toxicologists who are still doing old school toxicology.”

As a result, AGC, about a year ago, brought together a group of chemists, toxicologists and other government and private scientists to examine what the source describes as a “burgeoning wave” of new science on endocrine disruption with the goal of developing a tool for chemical makers to ensure in the development process that a chemical will not have effects on hormones.

The result is a five-tiered protocol that begins with what the source described as “quick and easy” Quantitative structure-activity relationship (QSAR) modeling and looking at a chemical’s structure, followed by in vitro high-throughput screening assays, validated and specialized cell-based assays, amphibian and fish tests, with the final tier being mammalian testing.

While chemical producers can run a new substance through as many or as few tiers as they choose, if a chemical passes through all the tiers, then it is quite likely to be safe, said Thaddeus Schung, a postdoctoral research fellow with NIEHS, speaking at the American Chemistry Society’s 15th Annual Green Chemistry and Engineering Conference in Washington, DC, June 22.

Schung said that the system aims to be a logical, consensus based tool to determine endocrine activity based on sound science. “Were trying to use this brain power here to come up with a sensible effort to . . . predict chemical toxicity.” Our hope, Schung said, is to “kick some of these chemicals out of production and make way for some new chemicals that are being developed by green chemistry.”

The AGC source echoes this, saying the protocol will provide an important new tool for chemical producers. As chemists develop these new materials “it’s really hard for them to know whether or not what they’ve designed has the potential to be an endocrine disruptor.”

“Green chemists are being asked to design the next generation of benign chemicals and they don’t have the tools to do it,” the source continues, adding that chemists are not toxicologists. “This is the new design criteria — you want to make chemicals that don’t act like hormones and don’t rewire people’s systems.”

And another source says that given the public backlash on products containing such endocrine disrupting chemicals such as bisphenol A (BPA), “industry is staying ahead of this now,” the source says. “They realize that this is the way we have to go.” – Jenny Hopkinson